review open access personalized ... - molecular cancer

REVIEW Open Access

Personalized therapies in the cancer “omics” eraAlberto Ocaña1,2, Atanasio Pandiella3*

Abstract

A molecular hallmark of cancer is the presence of genetic alterations in the tumoral DNA. Understanding howthese alterations translate into the malignant phenotype is critical for the adequate treatment of oncologic dis-eases. Several cancer genome sequencing reports have uncovered the number and identity of proteins and path-ways frequently altered in cancer. In this article we discuss how integration of these genomic data with otherbiological and proteomic studies may help in designing anticancer therapies “a la carte”. An important conclusionis that next generation treatment of neoplasias must be based on rational drug combinations that target variouspathways and cellular entities that sustain the survival of cancer cells.

ReviewA critical step towards defining a correct personalizedanticancer therapy is the identification of the genes andpathways altered in the tumour of the patient, and theelucidation of their particular oncogenic role. The suc-cess of molecular studies in identifying potential mole-cular targets for therapeutic intervention is exemplifiedby the developments in the treatment of chronic myelo-genous leukaemia (CML) [1]. This disease is character-ized by the presence of the Philadelphia chromosome,created by a translocation which provokes constitutiveactivation of the tyrosine kinase Abl. The identificationof this molecular alteration fostered the development ofdrugs such as Imatinib Mesylate that inhibit Abl kinaseactivity and successfully control the disease [2]. How-ever, in most solid tumours multiple genetic lesions areexpected to be required for tumour progression [3]. Infact, the clinical experience in the treatment of oncolo-gic diseases indicates that combinations of drugs thatact on different cellular targets demonstrate superiorityover single agent-based treatments [4]. Yet, these com-bined treatments are mostly based on empirical trialsand lack, in many instances, a biological rationale [5,6].Given the positive experience that molecular knowledgehas offered for the treatment of CML, efforts have beenmade to define the molecular alterations present in theDNA of distinct types of tumours. Here we will com-ment how novel high throughput techniques may help

in finding more adequate and less toxic personalizedanticancer therapies.

Somatic alterations in the cancer genomeIn designing proper anticancer therapies the clinical andthe preclinical researchers face several important ques-tions: How many genetic alterations exist in a tumour?How many of them are responsible of promoting tumourgrowth? How many should be targeted to eradicate thetumour? The availability of technologies that allow largescale sequencing and genomics analyses of severaltumours, together with strong bioinformatics tools andfunctional studies are contributing to answering thesequestions. Recent studies on the molecular profiling ofbreast and colon [7,8], lung [9-11], glioblastoma [12,13]and pancreatic [14] cancers have described alterations inmultiple genes and pathways important for the control ofcell number in these tumours. Although this is an alreadyknown concept, the value of these studies is that bysequencing of the whole transcriptome of individualtumours the researchers have uncovered the number ofmutated genes as well as their identity. In the analysis ofthe genomes of breast and colorectal cancers [7], between60 and 80 mutations that alter the amino acid sequence ofproteins (non-silent mutations) were detected in a singletumour (Table 1). Noteworthy, although some of thegenes were overlapping, most of them were not coinci-dent, not only when comparing breast and colon tumours,but also when comparing tumours of the same type butfrom distinct patients. It should however be mentionedthat these transcriptomic sequencing studies, while offer-ing important molecular information on individual

* Correspondence: [email protected] de Biología Molecular y Celular del Cáncer, CSIC-Universidad deSalamanca, Salamanca, Spain

Ocaña and Pandiella Molecular Cancer 2010, 9:202http://www.molecular-cancer.com/content/9/1/202

© 2010 Ocaña and Pandiella; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.

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tumours, must be complemented with other genomic ana-lyses, as they may, for example, miss the overexpression ofnon-mutated HER2 that is present in one out of fourpatients with breast cancer, and that represents a relevantclinical target [15]. Another more recent study identified alarger number (292 mutations in coding regions, of which187 were non-synonymous) of mutated genes in a cell lineof colorectal cancer [16]. It is possible that these differ-ences may stem from the fact that some works reportedresults from patients, while others used cell lines whichmay accumulate lesions along their in vitro establishment.On the other side, sequencing of acute myeloid leukaemia(AML) samples have identified 10 mutations in protein-coding mRNAs [17,18]. Additional massive sequencingefforts, such as those carried out by the International Can-cer Genome Consortium, will help in establishing a moreaccurate measurement of the average mutated genes/tumour.

By using bioinformatics analyses those authors indi-cated that most of the mutations in an individual breastor colon tumour were silent in terms of favouringtumour progression [7]. These analyses indicated thatnot more than 15 genes, that they term CAN genes(from “cancer” genes), are responsible for supportingtumour viability in each tumour. Some of the mutationsidentified affected genes that participate in the PI3K orNF�B routes, two pathways linked to cell survival/prolif-eration, and that are potential therapeutic targets (Table2). An important question that must be addressed ishow many of these CAN genes must be targetedfor efficient therapy of a tumour. On the basis of age-incidence data, some authors proposed that geneticalterations in 5-7 CAN genes may be required for solidtumour generation [19], and it is therefore expected thattargeting of these genes or some of their downstreamactor proteins may be therapeutically effective. We will

Table 1 Somatic mutations in cancer exomes and pathways affected

Tumour type(sample size)

Genesanalyzed

Average number ofmutated genes/

patient

Major pathways deregulated References

Breast (n = 11) 18,191 62 RTKs, PI3K, NF�B, [7]

Colorectal cancer(n = 11)

18,191 88 RTKs, PI3K, Cell adhesion, Cytoskeleton, Extracellular matrix [7]

Colorectal cancer(n = 1)

Genome 292 Transcription (SPDEF), Metalloproteases (MMP28), PI3K, BRAF [16]

Glioblastoma (n =22)

20,661 47 RTKs, PI3K, Cell cycle, DNA damage (p53), Neuronal-type pathways(ionic channels), IDH1

[13]

Pancreas (n = 24) 20,661 48 KRAS signalling, DNA damage control, Cell cycle, TGFb pathway, Wnt/Notch signalling, Cell adhesion and integrin signalling, MAPK signalling,Apoptosis

[14]

Glioblastoma (n =206)

601 selectedgenes

NA RTKs, NF1, DNA damage, PI3K, Cell cycle, methylation, mismatch repair [12]

Lung cancer (n =188)

623 genesimplicated incancer

NA RTKs, DNA damage control, RAS (K and N), NF1, LRP1B (lipidmetabolism), MAPK signalling, Wnt signalling, STK11 (Ser/Thr kinase)

[10]

Lung cancer (n =371)

NA NA Cell cycle, PI3K, RTKs, Tyrosine phosphatases, cAMP, Angiogenesis,NKX2-1 (pneumocyte differentiation)

[9]

Lung cancer (n =1)

Genome 134 Cell cycle (Rb), DNA damage (p53), DNA helicase CHD7 [11]

Mesothelioma (n =4)

15,000 6 DNA damage, Extracellular matrix, Mitochondrial reductase activity,proteasome, Apoptosis

[54]

Diverse cancers (n= 210)

518 kinases NA RTKs, JNK, MAPK,, BRAF, DNA damage control [20]

Renal cancer, clearcell (n = 101)

3544 NA Histone modifications (SETD2, JARID1C, UTX), VHL, NF2, HIF1A, PMS1(DNA mismatch repair), WRN and NBN (DNA double strand repair)

[55]

Diverse cancers (n= 3131)

NA NA Kinases, cell cycle, NF�B, Myc, Apoptosis, Cell adhesion, DNAmethylation, microtubule organization, transcription

[22]

Acute Myeloidleukaemia ((n = 1)

Genome 10 NRAS, NPM1, IDH1, CDC42, IMPG2, ANKRD46, LTA4H, FREM2, CEP170 [17,18]

Ovarian granulosacell tumours (n =4)

Genome NA FOXL2 [56]

RTKs: receptor tyrosine kinases. NA: not available


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comment later some biological studies that in fact sup-port the use of a restricted number of targettable pro-teins that fall within that latter number.Additional studies carried out in glioblastoma multi-

forme (GBM) [12,13] and pancreatic cancer [14], inaddition to describing the somatic alterations in theDNA, advanced to more precisely defining the molecu-lar pathways altered in these pathologies. Interestingly,in these tumours the number of mutated genes waslower (around 40 mutations/tumour) than in breast orcolorectal cancer. By using similar and complementarytechniques to search for point mutations, as well asgains and losses of genetic material, the two differentreports analyzing the genomes of patients with GBMsatisfyingly came to common conclusions [12,13]. Thesereports observed frequent alterations in three major sig-nalling pathways that control cell proliferation: thereceptor tyrosine kinase-PI3K route, the p53, and theretinoblastoma (RB) tumour suppressor pathways. Inter-estingly, some of these pathways were also found to par-ticipate in pancreatic as well as colon and breast cancertumours, indicating overlapping of signalling pathwaysthat may be critical in the genesis/progression of solidtumours. Interestingly also was the fact that mutationsin the genome of GBM patients accumulated in patientstreated with the alkylating agent temozolomide, a che-motherapeutic used in this pathology which is alsohighly mutagenic. Moreover, another study in which thegenes coding for kinases of patients with several types ofcancer were analyzed also showed that the highest pre-valence of mutations in the kinases corresponded toGBM patients treated with temozolomide [20]. Thisindicates that resistance mechanisms may develop in

Table 2 Drugs in clinical development against pathwaysidentified in genomic/proteomic studies

Receptor Tyrosine Kinases

Pan-ErbB receptors

CI-1033 Pfizer phase II[57,58]

BIBW-2992 Boehringer Ingelheim phase II[57,59]

Neratinib Wyeth-Ayerst phase III[60,61]

MET

MK-2461 Merck phase I/II[62]

XL184 Exelixis phase II/III[62]

MetMAb Genentech phase I[63]

FGFR

MK-2461 Merck phase I/II[62]

Brivanib BMS phase II[64]

K-RAS-RAF

PLX4032 Plexxikon Inc/Roche phase I[65]

PI3K-AKT Inhibitors-mTOR

Dual PI3K-mTOR

BEZ235 Novartis phase I/II[30,66,67]

XL765 Exelixis phase I[68]

SF1126 Semafore phase I/II[68,69]

BGT226 Novartis phase II[68]

PI3K Inhibitors

XL147 Exelixis phase I[68]

BKM120 Novartis phase I[68]

GDC0941 Genentech phase I[70,71]

AKT inhibitors

Perifosine Keryx phsae I/II[72-74]

GSK690693 GSK phase I[75-77]

MK2206 Merck phase I[68]

mTOR

OSI027 OSI Pharmaceuticals phase I[68]

AZD8055 AstraZeneca phase I/II[68]

MAPK inhibitors

MEK Inhibitors

CI-1040 Pfizer phase I/II[78,79]

AZD6244 AstraZeneca phase I/II[80,81]

XL518 Genentech phase I[71]

Cell Cycle

Flavopiridol Sanofi-aventis phase II/III[82]

SNS-032 BMS phase I/II[31]

R-547 Roche Phase I/II[83,84]

Seleciclib Cyclacel Pharmaceuticals Phase I/II[85]

Histone Deacetylase inhibitors

Vorinostat(SAHA)

Merck Phase I/II[86]

Romidepsin Gloucester Pharmaceuticals Phase I/II[87,88]

MGCD0103 MethylGene, Inc phase I/II[89]

LBH589 Novartis phase I/II[90,91]

Table 2 Drugs in clinical development against pathwaysidentified in genomic/proteomic studies (Continued)

Demethylating agents

Azacitidine Celgene approved[92,93]

Decitabine Eisai Pharmaceuticals approved[94]

DNA repair

PARP

Olaparib KuDOS Pharmaceuticals/AstraZeneca

phase II[95]

AG-014699 Pfizer phase II[96]

ATM

KU-55933 KuDOS Pharmaceuticals preclinical[97]

Matrix Metalloproteinases

Neovastat Æterna Laboratories phase III[98,99]

Prinomastat Pfizer phase III[98,100,101]


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these patients due to additive molecular alterations thatfavour the development of clones of cells resistant tothe action of classical treatments. The sequencing effortscarried out in GBM also identified isocitrate dehydro-genase 1 (IDH1) as a protein that could act in thepathogenesis of this disease [13,21]. Interestingly, IDH1was also found to be mutated in the genome of AMLpatients [18].In lung cancer, using single nucleotide polymorphism

(SNP) arrays, Weir et al. [9] analyzed the presence ofcopy-number alterations of chromosomal regions in alarge proportion (n = 371) of lung tumours, and foundfrequent gains or losses of chromosomal regions. Somegenomic alterations, such as copy number gain of chro-mosome 5p occurred in a high number of patients(60%). These alterations affected genes known to be fre-quently involved in lung cancer, such as EGFR/HER1,CCNE1, or KRAS. In addition, the paper describes anovel player in lung cancer pathophysiology, the NKX2-1 gene product, a transcription factor implicated in theformation of lung pneumocytes. Knocking down theexpression of this protein in NCI-H1925 lung cancercells decreased their ability to grow in an anchorage-dependent manner, indicating that this protein mayrepresent a novel lung cancer promoting oncogene, andan interesting novel therapeutic target. Another reportanalyzed somatic mutations of 623 genes in 188 lungcancer samples [10]. These genes were selected for theiralready known implication in oncogenesis. KRAS orEGFR were mutated in a substantial proportion ofpatients; but, in addition, several other genes not for-merly associated to lung cancer were identified, andincluded tumour suppressors (NF1, RB, ATM, andAPC), as well as tyrosine kinase genes (ERBB4, ephrinreceptor genes, KDR, FGFR4, and NTRK). Of note, 132of the 188 tumours had at least one mutation in genesthat participate in MAPK signalling. Also, mutations inmultiple genes of the Wnt pathway were observed in 29of the 188 samples. Frequent mutations were alsodetected in DNA damage response genes, includingTP53, and ATM. This clustering of mutations in certainpathways which play a role in oncogenesis points to thepossibility of interfering with them for the treatment oflung tumours. Moreover, from a more ample perspectivethe molecular studies mentioned above open outstand-ing possibilities in terms of better focusing on certaintargeted therapies for these tumours, based on drugsthat target components of the identified signalling path-ways. Another report confirmed the relevance of p53and Rb in lung cancer [11]. Here the researcherssequenced the whole genome of a lung cancer cell lineand found 22,910 somatic mutations, of which 134 wereincluded into coding exons, 94 of them causing changesin the primary sequence of the coded proteins.

An ample study of somatic copy number alterationsperformed on 3131 tumour samples, and also using highresolution SNP arrays identified a median of 12 gainsand loses in each patient tumour [22]. Frequent altera-tions in the control of cell cycle progression, apoptosis,DNA damage control, or kinase activity were reported.

The contribution of functional genomics to cancertherapyA strategy that has been recently developed to massivelyidentify potentially useful therapeutic targets is based onfunctional genomics studies using RNA-interference(RNAi) screenings. In one such functional screen basedon the knockdown of 2,924 genes selected for theirpotential implication in tumour generation/progression,Schlabach et al. identified between 80-150 gene productsimportant for tumour survival/proliferation [23]. Ofthem, 19 genes were shared by the three distincttumoral cell lines analyzed (two from colon cancer, andone from breast cancer). Interestingly, the list of theidentified proteins showed significant overlap betweendistinct tumoral cell lines, but were different from thoseidentified to be essential for the survival of normalbreast epithelial cells [23]. This indicates the existenceof qualitative differences between normal and malignantcells with respect to proteins that support their respec-tive viabilities. This is highly relevant from the therapeu-tic point of view, as it indicates that the targeting ofproteins that specifically support survival of cancer cellsis realistic, and may spare normal cells, therefore repre-senting an efficient and likely safe therapeutic strategy.In addition, these authors also found a certain degree ofoverlapping between proteins that support viability intumours from the same tissue origin. However, theyalso found proteins whose function was required to sus-tain viability of one tumour cell, but did not play a criti-cal survival role in others. Thus, knock down of theprotein phosphatase PP1 seriously affected survival ofHCC1954 colon cancer cell line, but did not substan-tially affect DLD-1 colon cancer cells. These results sup-port the concept of the distinct susceptibility of differenttumours, and stress the importance of adequately select-ing protein targets to achieve therapeutic success. Ana-logous functional genomic studies in haematologicalmalignancies led to the identification of the IRF4 andgenes regulated by this protein as potential therapeutictargets in multiple myeloma [24], and the demonstrationthat tyrosine kinases play an important role in sustain-ing AML vitality [25]. This last work is particularlyinteresting as the authors used fresh samples frompatients to identify, by also using RNAi techniques,potentially relevant drug targets. More ample RNAiscreening techniques, based on the knockdown of up to17,000 different genes [26], have allowed an almost


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universal analysis of the participation of the proteome intumour survival, and have identified pathways and pro-teins that participate in tumour proliferation/survival[27].In addition to finding potentially useful drug targets,

these RNAi-based functional genomic screens have alsobeen used to uncover mechanisms of drug resistance.Bernards and colleagues explored proteins involved intrastuzumab resistance in breast cancer and identifiedPTEN as one of the principal proteins whose lack offunction was linked to trastuzumab resistance [28], inagreement to previous reports [29]. Moreover, preclini-cal data indicated that combination of agents that targetHER2 and the PI3K route reverts resistance to trastuzu-mab [30].In spite of the value of these studies, one of the poten-

tial pitfalls is the identification of relevant targets invitro whose in vivo manipulation could be highly toxic.It is therefore mandatory to proceed into in vivo testingthe manipulation of those targets (Figure 1).

Biological findings support the use of combined targetedtherapiesAn important aspect of the functional genomics assaysis the finding of individual proteins whose targeting isdeleterious for the tumoral cell, opening the door to thedevelopment of drugs that by interfering with theiraction may be therapeutically relevant as single agents.However, as mentioned above, the clinical experiencesuggests that efficient cancer treatment usually relies onthe combination of agents that target distinct oncogenicnetworks. The fact that combination of agents may bemore efficient than single agent treatment may be dueto the heterogeneity of tumours, in some cases pro-moted by some anticancer treatments that either act asmutagens, as mentioned above in temozolomide-treatedpatients, or by the mutational heterogeneity within asingle tumour. This heterogeneity has been recently pro-posed as a limit for the value of high throughputsequencing efforts in individual tumours [31]. Thecross-talk between intracellular signalling pathwaysmainly activated by RTKs represents another reason toexplain the efficacy of combination strategies. It hasbeen reported that inhibition of certain pathways, suchas the mTOR route may lead to increased MAPK activ-ity [32]. Therefore, ablation of signals through bothroutes is required for efficient antitumoral action. More-over, combined inhibition of PI3K and MAPK routeshas shown superior antitumoral effect compared to indi-vidual targeting of either pathway [33].Elegant biological studies supporting that adequate

targeted drug combinations based on genomic profilingmay be effective in cancer treatment has been offered byreports from the Massagué group [34,35]. These

researchers used genomic and imaging techniques toanalyze a particularly relevant property of tumoral cells,i.e. metastatic dissemination. Their strategy was basedon the injection of a breast cancer cell line into thebloodstream of mice, and the selection of tumoralclones that homed to several organs. In their studies,genomic profiling identified signatures of genes thatwere particular of the cells that metastatized to a certaintissue. The researchers then selected some of thesegenes for further biological analyses, and suspected thatfour of them, Epiregulin, COX2, MMP1 and MMP2,represented therapeutic candidates in the case of lungmetastases. In fact, experiments of gene knockdownconfirmed the importance of these genes in breast can-cer tumour growth in nude mice. Interestingly, singleknockdown of only one of the coding mRNAs had littleeffect on the growth of these tumours as compared todouble knockdowns. But the most impacting resultswere obtained by quadruple knockdowns. Reduction ofthe expression of the four mRNAs coding for therespective proteins fully abrogated tumour growth.These genomic-functional studies were complementedwith targeted therapies aimed at neutralizing the activityof the four selected protein targets. Again, single agenttreatment was less effective than combinations in pre-venting extravasation and lung colonization by thetumoral cells. Also, combination of three targetedagents, expected to neutralize the function of all fourproteins, was more effective than dual combinations,and the triple combinations almost fully prevented lunginvasion by the tumoral breast cancer cell population.Another recent analogous study identified a set of genesthat mediate breast cancer metastasis to the brain [36].Interestingly, some of them (COX2 and HB-EGF) sharemolecular identity or properties with those formerlydescribed to participate in metastatic spreading to thelung. However, other proteins such as the sialystransfer-ase ST6GALNAC5 was specific for cells that metasta-tized to the brain, and could be involved in facilitatingcell passage through the blood brain barrier. The find-ings of Massagué and colleagues come in support of thewell established clinical concept that drug combinationsare superior in efficacy to single agents to treat solidtumours. The added value of their work is the use ofmolecular and biological tools to define and verify ade-quate targets for therapeutic intervention.

Combined targeted therapies guided by proteomicstudiesProbably the genomic portraits are insufficient in guid-ing the selection of antitumoral therapies. Indeed, stu-dies on receptor tyrosine kinase (RTK) targeting incancer have offered insights into the convenience ofcomplementing the genomic data with proteomic


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studies to establish efficient anticancer therapies. Stom-mel et al. [37] analyzed the phosphotyrosine content(indicative of activation) of 42 different RTKs in GBM.This disease may present alterations of the EGFR thatresult in its constitutive activation. However, response

rates to agents that target exclusively the EGFR arepoor. Stommel et al. found consistent activation of threeor more RTKs in 19 out of 20 GBM cell lines. TheseRTKs included the EGFR, ErbB3/HER3, platelet-derivedgrowth factor receptor a (PDGFRa), and MET. These

Oncogenic Alterations

“Omics” analyses

Targeted Drug Combinations

Mutation and copy number analyses

Identification of molecular alterations

Human Cancer

Proteomic studies

In vitro and in vivo validation(efficacy and safety)

Clinical Studies

Transcriptomic studies

Figure 1 Stepwise selection of antitumoral therapies based on individual oncogenic alterations. Analyses of oncogenic alterations inindividual tumour samples using “omics” techniques should allow the identification of candidate targets for therapeutic intervention.Experimental preclinical validation of these targets is critical in order to proceed to the clinical testing of drugs that act on the selected targets.


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researchers then explored the value of targeting theseactivated receptors using several in vitro models. Inhibi-tion of the activity of individual receptors had a mar-ginal effect on the growth properties of the GBM celllines. However, combination of drugs that targeted tworeceptors was superior to single agent treatments.Furthermore, triple combinations were more efficientthan double combinations, and practically abolishedtumour growth in soft agar colony forming assays. Theauthors conclude that coactivation of multiple RTKsmay sustain cell proliferation in GBM, and that ade-quate treatment of this pathology must include a carefulevaluation of the RTKs activated.In line with those findings, two additional reports

showed the importance of targeting multiple RTKs inbreast [38] and lung cancers [39]. Both studiesattempted to identify the mechanisms of resistance totherapies that target HER (Human EGFR-like Receptors)receptors. In the breast cancer study, resistance to gefiti-nib or erlotinib, agents that act on the EGFR/HER1, wasaccompanied by increased tyrosine phosphorylation ofErbB3/HER3 [38]. Similarly, gefitinib resistance in lungcancer was also found to be accompanied by ErbB3/HER3 signalling [39]. This up-regulation of ErbB3/HER3signalling was due to amplification of MET. Concomi-tant treatment with gefitinib and the MET inhibitorPHA665752 provoked a decrease in cell survival notobtained by single drug treatments. The fact that multi-kinase inhibitors have reached the oncology clinic addsvalue to these experimental results and paves the wayfor the development of multikinase targeting strategiesguided by proteomic analyses of the activation state ofthe kinome.

Limitations of targeted therapies based on genomicprofilingWhile the above mentioned studies offer unquestionableuseful information about relevant targets for therapeuticintervention in cancer, several factors that can limit theefficacy of targeted therapies must be considered. One isthe presence of molecular heterogeneity within a parti-cular tumour [40]. The well known genetic instability oftumour cells may be responsible for the generation ofdifferent subclones of tumoral cells that could be repre-sented at different amounts in the tumoral tissue (Figure2). Those present in higher amounts are expected to beresponsible for providing the genomic information,diluting the genomic landscapes of other tumoral cellspresent at lower amounts. The latter therefore escapedetection by those genomic/proteomic analyses andresult in tumour relapse, since targeted therapies areexpected to focus on alterations present in the mostlyabundant cells. Exemplifying this concept is the fact thatchronic exposure to gefitinib, an agent that targets the

EGFR, results in emergence of resistant lung cancercells bearing a mutation in the EGFR that renders thesetumoral cells insensitive to the drug [41]. Presumably,cancer initiating/stem cells represent another source offailure to targeted treatments, as they are expected torepresent a minority of the cellular constituents of thetumour. Strategies to identify drugs that target thesetumour initiating cells are being developed and mayrepresent useful additions to targeted therapies [42].Another factor that limits the efficacy of targeted

agents is the presence of parallel activation of down-stream pathways. A well characterized example is thepreclinical identification of the lack of antitumor activityof agents against RTKs when mutations at the K-RASand PI3K genes were present [43,44]. Translation ofthese studies to the clinic confirmed lack of activity ofanti-EGFR antibodies like cetuximab or panitumumabin colon cancer tumours with K-RAS mutations [45,46].These studies have been of much importance in selec-tion of anti-EGFR therapies in colorectal cancer, aspatients whose tumours express mutated forms ofK-RAS are now excluded from treatments based onanti-EGFR drugs. In addition, among colorectal tumourscarrying wild-type KRAS, other additional mutations ingenes participating in EGFR signalling may cause resis-tance to anti-EGFR therapies. Thus, mutation of BRAFor PIK3CA or loss of PTEN expression may result inresistance to EGFR-targeted monoclonal antibody treat-ment [47,48].Another important tumour component that is gaining

importance as a targettable cell type is the stromal com-partment. In multiple myeloma, a disease characterizedby the accumulation of tumoral plasma cells, the inter-action of these cells with the stroma is expected to becritical for sustaining survival of the myelomatous cells,and to provide drug resistance [49]. Moreover, treat-ments that target both the myeloma cell and the bonemarrow microenvironment, such as the proteasomeinhibitor bortezomib, or the immunomodulatory agentsderived from thalidomide, have shown anti-myelomaactivity and have reached the myeloma clinic [50]. Inter-estingly, genetic studies have demonstrated the presenceof genetic alterations in the bone marrow mesenchymalcells of patients with multiple myeloma, supporting theconcept that the stroma in the vicinity of the tumourmay be cancerized [51]. In other neoplastic pathologiessuch as breast cancer, mesenchymal stem cells havebeen shown to promote metastatic dissemination of thetumoral cells [52]. Moreover, recent studies perfomed inmyelodisplastic syndromes support the concept thatinitial alterations in the stromal compartment mayfavour the generation of secondary leukemias in amouse model, further supporting a potential role of thestroma in the pathophysiology of at least certain


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tumours [53]. Therefore, efficient antitumoral therapiesmust also take into consideration these variables inorder to achieve long lasting remissions.

Concluding remarksThe power of high scale “omics” analyses coupled withthe ample portfolio of targeted drugs under clinicaldevelopment and already approved offers hope for amore effective and individualized anticancer therapy. Itis rewarding to observe that sophisticated genomic, pro-teomic and biological studies reinforce the alreadyknown clinical strategy of using drug combinations totreat cancer patients (Figure 1). The molecular and bio-logical data herewith commented also offers clues as tohow many targets, pathways or functions should beattacked. The preclinical evidence that targeting fromone to four proteins may impede proliferation, survival

or invasion properties of cancer cells indicates thatthese cells depend on a limited number of proteins tocarry out these biological functions. That the studiesmentioned above have correctly targeted some of thesemolecules is beyond doubt. However, it is possible thattargeting other proteins could have a similar impact. Infact, few overlap exists between the molecules targetedin each of these individual papers, especially those thatused functional genomics to identify potential targets.This can be interpreted as to say that these papers havefound “a set”, (but not a unique “set”) of targets that aretherapeutically relevant. Finding a correct algorithm forthe combination of drugs that target a set of proteinscritical for sustaining cancer cells should be pursued.In conclusion, recent results using new “omic” techni-

ques support the future use of targeted drug combina-tions for the treatment of solid tumours. In our opinion

Normal stromal cell

Cancerized stromal cell

Cancer stem cell

Most abundant tumoral cells

Other tumoral cell subpopulations

Figure 2 Tumoral cell types that contribute to the heterogeneity of tumours. In addition to the most abundant tumoral cells, the geneticinstability of tumours is responsible for the establishment of genetically distinct tumoral cell subpopulations, which may escape genomicdetection as they may be diluted within the tumoral mass by the most abundant tumoral cells. Another important cellular component thatusually bears genomic and transcriptomic differences with respect to the majority of tumoral cells are the cancer initiating/stem cells. Thestromal cells that surround or are included into the tumoral mass may provide/receive proliferation/survival signals by crosstalking with tumoralcells. In certain neoplastic diseases, the stromal cells critically contribute to the survival or dissemination of the tumoral cells, and may beargenomic alterations that favour their tumor-supporting properties. These cancerized stromal cells and the rest of the cellular components oftumours must be targetted to achieve an efficient antitumoral response.


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to increase the efficiency of this process, it is critical toreach a close collaboration between academia, the phar-maceutical and biotechnological companies as well asregulatory authorities to develop rationale studies withdrug combinations based on strong preclinical data.

AcknowledgementsWe thank Prof. I. Tannock for the critical reading of the manuscript, andsuggestions. Work in AP lab receives support from the Ministry of Scienceand Education of Spain (BFU2006-01813/BMC and BFU2009-07728/BMC),from the ISCIII (RD06/0020/0041), and from the European Communitythrough the regional development funding program (FEDER). AO receivessupport from the Spanish Association Against Cancer (AECC), from theFISCAM grant program PI2007/41 and Proyectos de Investigación en Salud(PS09/02144). The CIC receives institutional support from the FundaciónRamón Areces.

Author details1Servicio de Oncología Médica, Complejo Hospitalario Universitario deAlbacete y unidad AECC, Albacete, Spain. 2Drug Development Program,Princess Margaret Hospital, Toronto, Canada. 3Instituto de Biología Moleculary Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain.

Authors’ contributionsBoth authors contributed equally to the writing of the paper. Both authorsalso read and approved the final manuscript.

Competing interestsThe authors declare that they have no competing interests.

Received: 5 May 2010 Accepted: 29 July 2010 Published: 29 July 2010

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doi:10.1186/1476-4598-9-202Cite this article as: Ocaña and Pandiella: Personalized therapies in thecancer “omics” era. Molecular Cancer 2010 9:202.

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